When females of the DDK inbred strain are mated with males of many other inbred strains, up to 95% of the resulting embryos die during preimplantation development. The reciprocal crosses, between DDK males and females of other inbred strains, are fully viable and fertile. The lethal trait segregates as 2 tightly-linked loci, one (1) encoding a DDK maternal "factor" (the "Ovum mutant" factor, OmDDK) that is present in the egg and that interacts with non-DDK alleles residing at the closely linked paternal gene, in trans, to cause lethality. We have located the maternal OmDDK factor as a member of the "Schlafen" (Slfn) gene family, identified previously as a family of T-cell growth and development regulators. We have also identified a unique haplotype, defined by 4 single nucleotide polymorphisms that exclude all but 24 kb of the Om region, associated with the lethally-interacting, non-DDK paternal gene. Interestingly, we have found that the DDK form of the paternal gene is the ancestral form. We propose to investigate the molecular mechanisms by which the Om maternal factor exerts its lethal effects on the "new" form of the paternal gene. We also plan to investigate the mechanism by which females carrying both the DDK form and the C57BL/6 form of the maternal gene give rise to 2 classes of ova, those that survive when fertilized by a C57BL/6 sperm and those that die when fertilized by a C57BL/6 sperm. The phenomenon of individual females producing ova of 2 different types, as well as the existence of different paternal gene response types, has implications for assisted reproductive technology in humans.